Neuropathology affecting primary motor cortex (M1) causes major neurological impairment including paralysis/paraplegia, epilepsy, and movement disorders including amyotrophic lateral sclerosis (ALS), a disease affecting upper motor neurons. Primary motor cortex (M1) is centrally involved in voluntary movement and other aspects of motor control (Denny-Brown, 1966;Phillips and Porter, 1977;Asanuma, 1989;Fetz et al., 2000;Sanes and Donoghue, 2000;Rizzolatti and Luppino, 2001;Schieber, 2001;Georgopoulos, 2002;Capaday, 2004;Curtis and Kleinfeld, 2006;Graziano, 2006;Kleinfeld et al., 2006). Local circuits of corticospinal neurons -- neurons projecting from cortex to the spinal cord -- in M1 mediate the key output pathway controlling movement of the body. Although the output of corticospinal neurons has been studied extensively, little is known about the local inputs to corticospinal neurons in any species. Hyperpolarization- activated cyclic nucleotide-gated (HCN) channels activate upon hyperpolarization, generating h-current (Ih) which can be regulated by multiple signal transduction pathways (Wahl-Schott &Biel, 2009). Ih has been observed in L5 neurons of somatosensory cortex (Spain et al., 1987: Berger et al., 2003), visual cortex (Soloman &Nerbonne, 1993b), and entorhinal cortex (Richter et al., 2000;Hamam et al., 2002). Evaluation of Ih and its effects on local circuit properties in corticospinal neurons of M1 has yet to be done. Since Ih resists changes in membrane potential, a narrow spatio-temporal integration window would be expected for local inputs to corticospinal neurons. Elucidating this will be critical for a detailed understanding of how M1 controls movement of the body, and holds the potential to reveal new therapeutic targets in the many neurological diseases that affect motor control such as ALS. ALS is a late onset neurodegenerative disease that results in progressive paralysis leading to premature death. Cortical hyperexcitability has been shown in ALS patients (Vucic et al., 2008, 2009), however, little is known about corticospinal circuits in ALS. The overall goal of these studies is to investigate in vitro circuit-level properties of mouse corticospinal neurons using use high-resolution laser scanning photostimulation (LSPS), slice electrophysiology, pharmacology, and anatomical labeling strategies. Preliminary data suggests that mouse corticospinal circuits (1) receive strong excitatory synaptic input from layer 2/3, (2) have intrinsic electrophysiology that is dominated by high expression of hyperpolarization-activated current (Ih), and (3) become altered in superoxide dismutase 1 (SOD1-693A) mutant mice, a mouse model of ALS. Thus the hypothesis for this proposal is that Ih produces class-specific synaptic integration properties in corticospinal neurons, and a corollary is that these properties are disrupted in a mouse model of ALS. The results of the proposed research will reveal fundamental mechanisms of local synaptic circuit physiology in M1 corticospinal neurons, providing a new basis for future studies of cortical dysfunction in disorders of motor control. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease affecting corticospinal neurons that results in progressive paralysis leading to premature death. Local circuits of corticospinal neurons -- neurons projecting from cortex to the spinal cord -- mediate the key output pathway controlling movement of the body by integrating diverse inputs from multiple sensory and motor-related systems. The results of the proposed research will reveal fundamental mechanisms of local synaptic circuit physiology in M1 corticospinal neurons, providing a new basis for future studies of cortical dysfunction in ALS.